Comparison of intestinal penetration of cortisol and convallatoxin: Demonstration of a transport mechanism for cardiotonic steroids

Abstract

1. 1. The dependence of the penetration of cortisol and convallatoxin (strophanthidin-α- l-rhamnoside) from the site of administration (mucosal or serosal solution) and from the steroid concentration was studied in the perfused small intestine of the rat in vitro (method of Fisher and Parsons. 2. 2. Within a concentration range of 5 to 400 μM, the penetration rate of cortisol is practically independent of the steroid concentration. The penetration from the perfusate into the serosal medium proceeds approximately three times more rapidly than in the reverse direction. 3. 3. The penetration rate of convallatoxin is markedly dependent on the glycoside concentration. Increasing the convallatoxin concentration in the perfusate from 5 to 400 μM causes a 95% decrease in penetration rate. The concentration dependence of the convallatoxin penetration from the serosal medium into the lumen is similar, but less pronounced. Therefore at a low glycoside administration on the serosal side, the penetration rate is smaller, but at a high concentration, it is ten times greater than in the normal direction. 4. 4. When convallatoxin is introduced into the perfusate, the glycoside content of the mucosal section of intestinal tissue is three times greater than in the serosal section. When convallatoxin is dissolved in the serosal medium, no significant differences within the different tissue layers can be observed. Under the latter conditions, the glycoside content of the tissue shows only a slight increase after the fist 15 min, while the glycoside penetration into the perfusion solution continues steadily. 5. 5. Protein assays in solution and tissues have shown that the anomalous penetration behaviour of convallatoxin cannot be ascribed to a release of cell- or protein-bound glycoside. 6. 6. A simple interpretation of these and previous results can be derived from the assumption that convallatoxin is absorbed by means of a transport mechanism wtih saturation kinetics (carrier transport). The reversal of the relationship of the penetration rates measured at high convallatoxin concentrations is thus explained by the saturation conditions of the transport mechanism on both sides of the luminal membrane of the mucosal cell. The relevance of a transport mechanism for cardiotonic steroids to the glycoside accumulation by the heart and to the theories of drug absorption is discussed.